This report provides an evidence-based review of current strategies to manage dry eye disease (DED). First-line management focuses on methods to replenish, conserve, and stimulate the tear film, with an emphasis on ocular supplements, which remain the cornerstone of DED treatment. Meibomian gland dysfunction, a primary contributor to DED, is typically treated with warm compresses and a wide variety of in-office treatments, including device-driven technologies to warm the eyelids, intense pulsed light therapy, low-level light therapy, and other new and emerging technologies. Lid hygiene treatments include lid wipes, anti-Demodex therapies, blepharoexfoliation, and topical antibiotics. DED caused by certain etiological drivers can benefit from anti-inflammatory therapies, including topical and oral corticosteroids, T-cell immunomodulatory drugs, and a wide variety of pharmacological agents, in addition to biologic tear substitutes such as autologous serum and platelet-rich plasma. Emerging therapies, such as neuromodulation via nasal neurostimulation and novel pharmacological treatments, offer potential future options. Advanced options, including amniotic membrane grafts and complex surgical methods, provide options for severe or refractory cases. Lifestyle modifications, including optimized blinking, dietary supplementation, and environmental adjustments, play a crucial role in long-term management. Patient education and adherence to treatment regimens remain essential for sustained symptom relief. The TFOS DEWS III prescribing algorithm provides an evidence-based framework to offer guidance to clinicians in selecting relevant interventions based on disease etiology that aim to provide targeted management of the relevant DED subtype(s) that an individual is experiencing.

A standard approach to the diagnosis of dry eye disease across eye care practitioners is critical to reassuring the patient, providing consistency between practitioners and informing governments as to the true prevalence and resulting healthcare needs. The Tear Film & Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) III has reviewed the evidence-base since their previous reports published in 2017 and revised the definition to "Dry eye is a multifactorial, symptomatic disease characterized by a loss of homeostasis of the tear film and/or ocular surface, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities are etiological factors." Key features from the definition include that dry eye disease is multifactorial, is a disease and not a syndrome and is always symptomatic. Differential diagnosis and ocular examination guidance is given along with the risk factors that should be discussed with the patient. The recommended screening questionnaire is the OSDI-6 with a cut-off score ≥4. A positive result together with a non-invasive breakup time <10s or alternatively tear film hyperosmolarity (≥308mOsm/L in either eye or an interocular difference >8mOsm/L) or alternatively >5 corneal fluorescein and/or >9 conjunctival lissamine green punctate spots and/or lid margin lissamine green staining of ≥2mm length & ≥25 % width, gives a diagnosis of dry eye. Subclassification was separated into tear film deficiencies (lipid, aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid margin) and ocular surface abnormalities (anatomical misalignment, neural dysfunction, ocular surface cell damage/disruption and primary inflammation/oxidative stress) components, with appropriate clinical tests and cut-offs provided to identify these etiological drivers in an individual, to inform appropriate management and therapy.

This article presents an executive summary of the conclusions and recommendations of the third Tear Film and Ocular Surface Society Dry Eye Workshop (TFOS DEWS III) reports, published in the American Journal of Ophthalmology (AJO) in the second quarter of 2025. These reports describe an updated, evidence-based consensus understanding of dry eye disease, together with scientifically-supported strategies for its clinical diagnosis and managagement. The three comprehensive TFOS DEWS III reports and accompanying editorial are freely available for download from the AJO website (www.ajo.com).

This digest summarizes the interdisciplinary research in dry eye disease (DED) published since the 2017 TFOS DEWS II reports. It comprises 7 topics including Sex, Gender, and Hormones; Epidemiology; Pathophysiology; Tear Film; Pain and Sensation; Iatrogenic Dry Eye; and Clinical Trial Design and explores how each of these inform diagnostic methodology, disease subtype, and management of DED. Sex- and gender-related differences significantly influence the ocular surface due to hormones, sex chromosomes, sex-specific autosomal factors, epigenetics, care-seeking behaviors, and service use. Epidemiologic data reveal that DED prevalence varies by age and sex, influenced by diagnostic criteria and the multifactorial nature of the disease. New risk factors for DED include environmental, iatrogenicity, systemic diseases, and lifestyle domains. Pathophysiological distinctions between aqueous deficient and more evaporative forms of DED have been clarified, with the latter most commonly characterized by a muted inflammatory response at the ocular surface, meibomian gland dysfunction, and conceivably phenotypic changes in corneal epithelial cells. There is an expanding role for metabolic, hormonal, physical, neural and cellular stresses, including hyperosmolarity, mitochondrial stress, and neurogenic inflammation. Advancements in tear film research recommend new approaches to understanding DED pathogenesis and identifying biomarkers, such as microRNAs. Ocular pain perception is linked to structural integrity of corneal nerves, functional capacities of neurons, and activity of the central and peripheral nervous systems. Iatrogenic DED can result from medications, contact lenses, and surgical procedures. Clinical trials now emphasize aligning design and end points with DED subtypes and therapeutic mechanisms, with new therapeutics and trial designs under consideration.

Purpose: To study the association between tear film hyperosmolarity and ocular light scatter in a cataract surgery population. Patients and Methods: Contiguous, 20-second objective scatter index (OSI) scans were recorded in hyperosmolar (>= 320 mOsm/L) and normal subjects (< 308 mOsm/L) with cataract nuclear opacity >= 3. OSI was measured at screening, baseline and 90 days following surgery. Along with symptoms of ocular surface disease, slit-lamp examination included corneal staining (0- 3), tear film breakup time (TBUT) and evaluation of meibomian gland disease (MGD). An additional cohort of hyperosmolar subjects were measured for OSI at screening, baseline, and 5, 10, 15 and 30 minutes following instillation of 0.18% sodium hyaluronate (HA). Results: Thirty-one eyes of 31 patients were included. There was a significant difference in post-operative OSI variation when comparing hyperosmolar (0.65 +/- 0.30, N=11) to normal subjects (0.33 +/- 0.11, N=10, p=0.005). Of note, there were no significant differences in OSI variation when subjects were sorted by staining (p=0.9), TBUT (p=0.7), symptoms (p=0.7), or MGD status (p=0.9). Instillation of 0.18% HA (N=10) did not alter OSI at 5 minutes, but significant reductions in OSI of 28.8%, 38.5% and 36.7% (all p < 0.001) were observed at 10, 15 and 30 minutes. Conclusion: Hyperosmolar patients exhibited significantly increased variation in light scatter following cataract surgery that was undifferentiated by staining or TBUT. Elevated osmolarity may be indicative of light scatter equivalent to that of a grade 2- 3 cataract.

Purpose:To understand the impact of subjectivity on diagnosis rates of dry eye disease (DED) in an unbiased population. Patients and Methods:A multicenter study enrolled 818 subjects with complete report forms (465 females, 67.1 ± 16.7 years, 353 males, 65.0 ± 15.9 years). Subjects were evaluated for staining, TBUT, tear osmolarity, meibomian gland disease, and OSDI. Results:Physicians diagnosed 48.7% of subjects as having DED, ranging from 42.9% to 62.3% between sites. Positivity rates for staining (≥ grade 1) ranged from 41.3% to 84.1% (mean = 0.8 ± 0.9 grade), TBUT (<10s) ranged from 39.1% to 61.6% (mean = 10.4 ± 6.6 seconds), osmolarity (>308 mOsm/L) ranged from 63.7% to 72.4% (mean = 319.7 ± 20.8), MGD grading ranged from 28.9% to 51.3% (mean = 0.5 ± 0.7), and symptoms measured by OSDI ranged from 57.6% to 71.0% (mean = 23.5 ± 20.5) between sites. Tear osmolarity was the most consistent between sites (max/min positivity = 114%), followed by OSDI (123%), TBUT (158%), MGD (178%), and staining (204%). DED markers were uncorrelated (average r2 = 0.05 ± 0.07). A substantial number of subjects (N = 110) exhibited positive symptoms (OSDI = 32.4 ± 15.7) and hyperosmolarity (338.1 ± 20.1 mOsm/L) but no other obvious signs of DED (MGD grade = 0.2 ± 0.4, TBUT = 13.5 ± 7.0 seconds, staining grade = 0.4 ± 0.5). Conclusion:Subjective signs of DED varied considerably, whereas objective measurements of OSDI and osmolarity were the most consistent between sites. A large proportion of subjects exhibited high symptoms and hyperosmolarity but no other obvious signs of dry eye disease, most of whom were undiagnosed by clinical assessment without access to the osmolarity measurement.

The Tear Film & Ocular Surface Society (TFOS) Workshop entitled ‘A Lifestyle Epidemic: Ocular Surface Disease’ was a global initiative undertaken to establish the direct and indirect impacts of everyday lifestyle choices and challenges on ocular surface health. This article presents an executive summary of the evidence-based conclusions and recommendations of the 10-part TFOS Lifestyle Workshop report. Lifestyle factors described within the report include contact lenses, cosmetics, digital environment, elective medications and procedures, environmental conditions, lifestyle challenges, nutrition, and societal challenges. For each topic area, the current literature was summarized and appraised in a narrative-style review and the answer to a key topic-specific question was sought using systematic review methodology. The TFOS Lifestyle Workshop report was published in its entirety in the April 2023 and July 2023 issues of The Ocular Surface journal. Links to downloadable versions of the document and supplementary material, including report translations, are available on the TFOS website: http://www.TearFilm.org.

Proteoglycan 4 (PRG4, lubricin) is a mucin-like glycoprotein present on the ocular surface that has both boundary lubricating and anti-inflammatory properties. Full-length recombinant human PRG4 (rhPRG4) has been shown to be clinically effective in improving signs and symptoms of dry eye disease (DED). In vitro, rhPRG4 has been shown to reduce inflammation-induced cytokine production and NFκB activity in corneal epithelial cells, as well as to bind to and inhibit MMP-9 activity. A different form of recombinant human lubricin (ECF843), produced from the same cell line as rhPRG4 but manufactured using a different process, was recently assessed in a DED clinical trial. However, ECF843 did not significantly improve signs or symptoms of DED compared to vehicle. Initial published characterization of ECF843 showed it had a smaller hydrodynamic diameter and was less negatively charged than native PRG4. Further examination of the structural and functional properties of ECF843 and rhPRG4 could contribute to the understanding of what led to their disparate clinical efficacy. Therefore, the objective of this study was to characterize and compare rhPRG4 and ECF843 in vitro, both biophysically and functionally. Hydrodynamic diameter and charge were measured by dynamic light scattering (DLS) and zeta potential, respectively. Size and molecular weight was determined for individual species by size exclusion chromatography (SEC) with in-line DLS and multi-angle light scattering (MALS). Bond structure was measured by Raman spectroscopy, and sedimentation properties were measured by analytical ultracentrifugation (AUC). Functionally, MMP-9 inhibition was measured using a commercial MMP-9 activity kit, coefficient of friction was measured using an established boundary lubrication test at a latex-glass interface, and collagen 1-binding ability was measured by quart crystal microbalance with dissipation (QCMD). Additionally, the ability of rhPRG4 and ECF843 to inhibit urate acid crystal formation and cell adhesion was assessed. ECF843 had a significantly smaller hydrodynamic diameter and was less negatively charged than rhPRG4, as assessed by DLS and zeta potential. Size was further explored with SEC-DLS-MALS, which indicated that while rhPRG4 had 3 main peaks, corresponding to monomer, dimer, and multimer as expected, ECF843 had 2 peaks that were similar in size and molecular weight compared to rhPRG4's monomer peak and a third peak that was significantly smaller in both size and molar mass than the corresponding peak of rhPRG4. Raman spectroscopy demonstrated that ECF843 had significantly more disulfide bonds, which are functionally determinant structures, relative to the carbon-carbon backbone compared to rhPRG4, and AUC indicated that ECF843 was more compact than rhPRG4. Functionally, ECF843 was significantly less effective at inhibiting MMP-9 activity and functioning as a boundary lubricant compared to rhPRG4, as well as being slower to bind to collagen 1. Additionally, ECF843 was significantly less effective at inhibiting urate acid crystal formation and at preventing cell adhesion. Collectively, these data demonstrate ECF843 and rhPRG4 are significantly different in both structure and function. Given that a protein's structure sets the foundation for its interactions with other molecules and tissues in vivo, which ultimately determine its function, these differences most likely contributed to the disparate DED clinical trial results.

Glaucoma is a common disease with an increasing prevalence [1]. Ocular surface disease (OSD) is also common, and its prevalence is increasing [2,3], due in part to the adverse effects of topical glaucoma medications [4,5]. Given this glaucoma/OSD association, David A. Sullivan, MS, PhD (Boston, MA, USA) and Amy Gallant Sullivan (Paris, France) on behalf of the Tear Film & Ocular Surface Society (TFOS), and in collaboration with Miriam Kolko, MD, PhD (Copenhagen University Hospital & University of Copenhagen, Denmark), organized a one-day meeting which was held on Saturday, October 22, in Cernobbio, Italy. This meeting focused on the impact of glaucoma medications on the ocular surface, and how OSD can influence glaucoma treatment. The term "ocular surface" encompasses the surface (cornea and conjunctiva), tear film, and adnexa (lacrimal and meibomian glands). The speakers included internationally renowned glaucoma and OSD experts. The evidence-based proceedings of this meeting are presented in this TFOS Experts' Meeting report.

In this report the use of eye cosmetic products and procedures and how this represents a lifestyle challenge that may exacerbate or promote the development of ocular surface and adnexal disease is discussed. Multiple aspects of eye cosmetics are addressed, including their history and market value, psychological and social impacts, possible problems associated with cosmetic ingredients, products, and procedures, and regulations for eye cosmetic use. In addition, a systematic review that critically appraises randomized controlled trial evidence concerning the ocular effects of eyelash growth products is included. The findings of this systematic review highlight the evidence gaps and indicate future directions for research to focus on ocular surface outcomes associated with eyelash growth products.

To analyze and review the clinical features and main outcomes of laminar resorption from the UK osteo-odonto-keratoprosthesis (OOKP) cohort.A retrospective review of case records was undertaken for patients who underwent keratoprostheses between 1996 and 2014 at the Sussex Eye Hospital, Brighton, UK. The main clinical outcomes of resorption, including its clinical signs, complications, treatments, and laminar survival, were evaluated.Sixty-four patients (25-females, 39-males) were included, and in total, 74 laminae (3-tibial, 11-allografts, 60-autografts) were implanted. The age of the patients ranged from 20 to 91 years. Focal laminar thinning was the first sign of detectable resorption in 50% of autografts and 27% of allografts. All the tibial grafts and 55% of allografts presented with complications of resorption like endophthalmitis and aqueous leakage as the first signs of resorption. The survival of first implanted autografts was 82.4%(±6.3%) at 18 years, which was enhanced to 91.5%(±5.0%) by prophylactic exchanges of critically resorbed laminae with new laminae. Visual acuity survival analysis did not reveal a statistically significant difference between grafts with and without resorption for all graft types (p = 0.825). Patients treated with Alendronic acid and acetazolamide demonstrated trends toward the slower progression of resorption, but this was not statistically significant.Focal laminar thinning was the common presenting feature of resorption in autografts. Timely replacement of the resorbed laminae with new laminae should be considered to avoid complications. Alendronic acid supplementation may be considered in high-risk cases of resorption to reduce further progression.

We recently discovered that by changing environmental signals, differentiated immortalized human meibomian gland epithelial cells (IHMGECs) de-differentiate into proliferating cells. We also discovered that following exposure to appropriate stimuli, these proliferative cells re-differentiate into differentiated IHMGECs. We hypothesize that this plasticity of differentiated and proliferative IHMGECs is paralleled by very significant alterations in cellular gene expression. To begin to test this hypothesis, we compared the gene expression patterns of IHMGECs during differentiation and proliferation. IHMGECs were cultured for four days in either differentiating or proliferating media. After four days of culture, cells were processed for the analysis of gene expression by using Illumina BeadChips and bioinformatic software. Our study identified significant differences in the expression of more than 9200 genes in differentiated and proliferative IHMGECs. Differentiation was associated with significant increases in the expression of specific genes (e.g. S100 calcium binding protein P; 7,194,386-fold upregulation) and numerous ontologies (e.g. 83 biological process [bp] ontologies with ≥100 genes were upregulated), such as those related to development, transport and lysosomes. Proliferation also led to a significant rise in specific gene expressions (e.g. cathelicidin antimicrobial peptide; 859,100-fold upregulation) and many ontologies (115 biological process [bp] ontologies with ≥100 genes were upregulated), with most of the highly significant ontologies related to cell cycle (z scores > 13.9). Our findings demonstrate that gene expression in differentiated and proliferative IHMGECs is extremely different. These results may have significant implications for the regeneration of HMGECs and the reversal of MG dropout in MG dysfunction.

Purpose We recently discovered that a hypoxic environment is beneficial for meibomian gland (MG) function. The mechanisms underlying this effect are unknown, but we hypothesize that it is due to an increase in the levels of hypoxia-inducible factor 1α (HIF1α). In other tissues, HIF1α is the primary regulator of cellular responses to hypoxia, and HIF1α expression can be induced by multiple stimuli, including hypoxia and hypoxia-mimetic agents. The objective of this study was to test our hypothesis. Methods Human eyelid tissues were stained for HIF1α. Immortalized human MG epithelial cells (IHMGECs) were cultured for varying time periods under normoxic (21% O2) or hypoxic (1% O2) conditions, in the presence or absence of the hypoxia-mimetic agent roxadustat (Roxa). IHMGECs were then processed for the analysis of cell number, HIF1α expression, lipid-containing vesicles, neutral and polar lipid content, DNase II activity, and intracellular pH. Results Our results show that HIF1α protein is present in human MG acinar epithelial cells in vivo. Our findings also demonstrate that exposure to 1% O2 or to Roxa increases the expression of HIF1α, the number of lipid-containing vesicles, the content of neutral lipids, and the activity of DNase II and decreases the pH in IHMGECs in vitro. Conclusions Our data support our hypothesis that the beneficial effect of hypoxia on the MG is mediated through an increased expression of HIF1α.

PURPOSE:We discovered that dihydrotestosterone (DHT) decreases the ability of lipopolysaccharide, a bacterial toxin, to stimulate the secretion of leukotriene B4, a potent proinflammatory mediator, by immortalized human meibomian gland epithelial cells (IHMGECs). We hypothesize that this hormone action reflects an androgen suppression of proinflammatory gene activity in these cells. Our goal was to test this hypothesis. For comparison, we also examined whether DHT treatment elicits the same effect in immortalized human corneal (IHC) and conjunctival (IHConj) ECs. METHODS:Differentiated cells were cultured in media containing vehicle or 10 nM DHT. Cells (n = 3 wells/treatment group) were then processed for RNA isolation and the analysis of gene expression by using Illumina BeadChips, background subtraction, cubic spline normalization and Geospiza software. RESULTS:Our results demonstrate that DHT significantly suppressed the expression of numerous immune-related genes in HMGECs, such as those associated with antigen processing and presentation, innate and adaptive immune responses, chemotaxis, and cytokine production. DHT also enhanced the expression of genes for defensin β1, IL-1 receptor antagonist, and the anti-inflammatory serine peptidase inhibitor, Kazal type 5. In contrast, DHT had no effect on proinflammatory gene expression in HCECs, and significantly increased 33 gene ontologies linked to the immune system in HConjECs. CONCLUSIONS:Our findings support our hypothesis that androgens suppress proinflammatory gene expression in IHMGECs. This hormone effect may contribute to the typical absence of inflammation within the human meibomian gland.